α-glucosidase inhibitors

ABSTRACT

This invention relates to novel polyglycosidyl derivatives of 1-deoxy-nojirimycin, to the processes for their preparation and to their end-use applications, particularly as to their use in the treatment of diabetes.

This invention relates to novel polyglycosidyl derivatives of1-deoxy-nojirimycin, to the processes for their preparation and to theirend-use applications, particularly as to their use in the treatment ofdiabetes.

More specifically this invention relates to novel polyglycosylderivatives of 1-deoxy-nojirimycin, to the chemical processes for theirpreparation, to their α-glucosidase inhibiting properties, and to theirend-use application in the treatment of diabetes, obesity and thosediseases associated with retroviruses, particularly the HIV virusreported to be causative of acquired immune deficiency syndrome (AIDS).

UK Patent Application GB 2 088 365 A discloses a bisglucosylmoranolinederivative useful as a remedy for diabetes mellitus.

European Patent Application Number 87112480.6 disclosesglucosylmoranoline derivatives useful as a remedy for diabetes.

Still more specifically this invention relates to the novel 1-deoxynojirimycin derivatives of the formula I ##STR1## andthe-pharmaceutically acceptable acid addition salts thereof wherein

n is zero, 1 or 2,

R is a glycosyl moiety containing 1 to 3 hexose or pentose units, saidunits optionally bearing an ether or acyl radical at the anomeric carbonatom of the terminal hexose or pentose unit, and one of R₁ and R₂ is Hand the other is α-D-glucopyranosyl. The glycosyl moiety represented by"R" in Formula I are radicals which contain from 1 to 3 hexose orpentose units which optionally bear an ether or an acyl radical at theanomeric carbon atom of the terminal hexose or pentose moiety.

Acid addition salts are those salts forms with such inorganic acids as,for example, hydrochloric, hydrobromic, sulfuric, phosphoric and likeacids; with organic carboxylic acids such as, for example, acetic,propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric,maleic, tartaric, citric, ascorbic, maleic, hydroxymaleic anddihydroxymaleic, benzoic, 2-acetoxybenzoic, mandelic and like acids; andwith organic sulfonic acids such as methanesulfonic acid andp-toluenesulfonic acid.

In general, the mono-, di- or trisaccharide moiety (i.e., the glycosylmoiety defined by R) may be attached directly -- or thru a (CH₂)_(n)alkylene bridge -- to the nitrogen atom of the 1-deoxynojirimycin moietythru either an exocyclic or ring carbon atom of the pentose or hexosering thereby forming a variety of position isomers for each individualglycosyl moiety. Also, similar or dissimilar pentose or hexose moietiesmay be linked to each other thru a glycosidic oxygen bridge wherein thebridging oxygen atom is attached to an exocylic and/or endocyclic carbonatom of the pentose or hexose moiety of which the glycosyl radical iscomprised; again the position isomers all being contemplated as beingwithin the scope of this invention.

Exemplary of glycosyl radicals contemplated by the "R" designation inFormula I are such monosaccharides as 6- or 4-glucosyl, 6- or4-galactosyl, 4-fucosyl, 1-, 2- or 6-fructosyl, 6- or 4-mannosyl,4-ribosyl, 4-arabinosyl, 4-xylosyl, 6- or 4-allosyl, 6- or 4-altrosyl,6- or 4-gulosyl, 6- or 4-idosyl, 6- or 4-talosyl and 4-1-yxosyl, suchdisaccharides as 4- or 6-isomaltosyl, 4- or 6-trehalosyl, β4- or6-cellobiosyl, maltosyl, and such trisaccharides as maltotriosyl andcellotriosyl. Preferred glycosyl radicals are 6- or 4-glucosyl, 1- or6-fructosyl, 6- or 4-maltosyl and 6- or 4-isomaltosyl. Ether derivativesare those derivatives wherein the hydroxyl group attached to theanomeric carbon atom is etherified and include the C₁₋₈ alkylderivatives, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl,cyclohexyl, cyclohexylmethyl, t-butyl, isobutyl, isopropyl and aromaticderivatives such as phenyl and benzyl and the like. Acyl derivatives,such as those formed at the anomeric carbon atom by reaction of the freehydroxy radical with C₁₋₈ alkanoic acids or benzoic acids, are alsocontemplated even though such acylated moieties may easily be removedfrom the glycosyl radical. Preferred acyl radicals are those formed withacetic or benzoic acids, although acyl radicals formed from such acidsas propionic, n-butyric, isobutyric, n-valeric, hexanoic andphenylacetic acid are contemplated.

The α-D-glucopyranosyl moiety of R₁ and R₂ has the structural formula##STR2## the wavy line indicating the bond by which it is attached tothe oxygen of either the 4- or 6- positions of the 1-deoxynojirimycinmoiety.

The final products of formula I may be prepared by one of two alternatemethods which are depicted by Reaction Scheme A and B. Reaction Ainvolves the condensation of a 1-halo (preferablybromo)-2,3,4-trihydroxy-protected (preferablybenzyl)-6-O-t-butyldimethylsilyl-α-D-glucopyranosyl derivative with anN-R'-substituted -2,3,4-trihydroxyprotected (preferablybenzyl)-6-O-hydroxyl-1-deoxynojirimycin derivative (R' being anOH-protected glycosyl moiety as previously defined) to produce theexpected hydroxy-protected analogs of formula I which are thendeprotected to produce the desired compounds embraced by formula I.Reaction Scheme B involves the condensation reaction of a haloderivative of a glycosyl with a 1-deoxynojirimycin bearing anα-D-glucopyranosyl moiety to produce the desired compounds of formula I.In essence, Reaction Scheme A illustrates the preparation of compoundsof formula I wherein the α-D-glucopyranosyl moiety is attached to the1-deoxynojirimycin moiety via the 6-position linkage (i.e., R₁ isα-D-glucopyranosyl and R₂ is H), whereas Reaction Scheme B illustratesthe preparation of compounds of formula I wherein the α-D-glucopyranosylmoiety is attached to the 1-deoxynojirimycin moiety via the 4-positionlinkage (i.e., R₂ is α-D-glucopyranosyl and R₁ is H).

For convenience, and to better teach the preparation of the compounds ofthis invention, Reaction Schemes A and B depict specific reactants.However it is to be understood that the schemes have generalapplicability to the various glycosyl moieties (as defined by R onformula I) it being understood to those of ordinary still in the artthat the hydroxyl groups of any of the R-glycosyl moieties will besuitably protected and deprotected as indicated for the specificreactants used in the Reaction Schemes shown below. ##STR3## whereinB_(n) is a benzyl or equivalently functioning hydroxy-protecting groupand t-Bu is tertiary butyl. ##STR4## wherein the wavy line of formula 10and 11 indicates an α-or β-methyl glycoside at the anomeric carbonposition (or the α- and β-free hydroxy analog of the glycoside moiety).

In effecting Reaction Scheme A, step (a) entails converting the6-hydroxy moiety of 1,5-dideoxy-1,5-(6-deoxy-1-O-methyl-6-α-D-glucopyranosyl)imino!D-glucitol (2) to itsO-t-butyldimethylsilyloxy analog (3) by reaction witht-butyldimethylchlorosilane in the presence of imidazole indimethylformamide. Step (b) converts (3) to its benzylated analogs (4)by reaction with 6 equivalents of benzyl bromide and 6 equivalents ofsodium hydride in the presence of n-tetrabutyl ammonium iodide indimethylformamide at room temperature, preferably overnight and theresulting product hydrolyzed with aqueous ammonium chloride to thedesired products which, when subjected to step (c) involving thereaction with n-tetrabutyl ammonium fluoride trihydrate intetrahydrofuran yields compounds (5). Step (d) involves the reaction ofcompounds (5) with2,3,4-tri-O-benzyl-6-O-t-butyldimethylsilyl-α-D-glucopyranosyl bromide(compounds 6) in the presence of diisopropylethylamine in ethanol-freechloroform at room temperature to produce compounds (7) which are thendeprotected by standard debenzylation techniques such as catalytichydrogenation in ethanol using palladium on carbon until up take ofhydrogen is complete (about 7 days) or by transfer hydrogenation usingformic acid in methanol with Pd/C. When transfer hydrogenationtechniques are utilized the products are in the form of their ammoniumsalts and must be neutralized, preferably using ion exchange resins,such as Dowex AG 1X8 OH.sup.⊖ form.

In effecting Reaction Scheme B, the 1-deoxy nojirimycin derivative (9)is reacted with the appropriate bromo derivative of an R-glycosylmoiety, e.g. compound (10), in dimethylformamide at about 80° C. forabout 48 hours to produce the desired compounds (11).

In general the starting materials such as compounds (2) are knowncompounds. In those instances wherein the 1-deoxy nojirimycin reactantsanalogous to compounds of formulae 2,3,4 and 5 which contain aN-glycosyl moiety (i.e. R is glycosyl) other than that shown in formulae2, 3, 4, 5, 7, 8, 10 and 11, such compounds may also be prepared bymethods analogously known in the art. It is preferred to condense anappropriately hydroxy protected 1-deoxy-nojirimycin (2) with anappropriately hydroxyprotected activated glycosyl moiety, preferablyusing a trillate or halide, preferably the iodide, but including bromideand chloride and including mesylates or rosylates or other equivalentlyfunctioning moieties appreciated by those of ordinary skill in the art.In those instances wherein the 1-deoxy-nojirimycin is coupled with atrillate the reaction is effected by refluxing an admixture of equimolarquantities of the reactants in an alcohol- and water-free solvent,preferably a chlorinated solvent such as chloroform, under an inertatmosphere, preferably under nitrogen or argon, for about 1 to 3 daysuntil the reaction is completed. Following standard procedures for theisolation and purification of the reaction products, the protectinggroups are removed to obtain the desired product. Debenzylation isreadily effected with standard techniques such as catalytichydrogenation in an appropriate solvent, e.g. ethanol, using a catalystsuch as palladium on carbon, or by transfer hydrogenation usingcyclohexene and methanol. In those instances wherein esters wereutilized (partially or completely) as the hydroxy protecting groups, itis preferred to first remove the ester group by treatment with an alkalialkoxide, e.g. sodium methoxide, in methanol to hydrolyze the esters andthen deprotect the benzyl ethers using the foregoing hydrogenationprocedures.

In those instances wherein a glycosyl halide is coupled with the1-deoxy-nojirimycin the reaction is effected by heating theappropriately hydroxy protected reactants in dry dimethylformamide (DMF)or other equivalently functioning solvent, at about 60°-90° C. for about12 to 36 hours, said heating taking place using excess amounts of a weakbase (K₂ CO₃) or a molecular sieve, preferably using excess molaramounts of the halide (up to three times) relative to the amine.

The foregoing reactions are illustrated by the following reactionschemes C and D. ##STR5##

Otherwise depicted, the reaction scheme may more generally be depictedby the following reaction scheme ##STR6## wherein X is a halide(preferably iodide) or a trillate, n is zero, one or two and R' is aglycosyl moiety (as defined by Formula I) having its OH groups protectedwith a benzyl protecting group, and Bn is benzyl and compound (12) is asdepicted in Reaction Schemes C and D.

Appropriately hydroxy protected glycosyl halides (16) and triflates (13)are those glycosyl radicals (mono-, dior trisaccharides of Formula I)where in the hydroxy groups have been protected with an ester or ethermoiety. Preferred esters are the acetate or benzoate esters althoughother alkanoyl esters, particularly those containing up to six carbonatoms, may be used. The preferred ether is the benzyl ether. Suchprotected compounds may be prepared by standard procedures very wellknown and understood in the art.

The glycosyl triflates (of which compound 13 is representative) areprepared by standard procedures such as by reaction of an hydroxyprotected glycosyl with trifluoromethylsulfonate anhydride in achlorinated solvent with pyridine for about 1-3 hours at about -78° C.to -10° C. (It is to be noted that the anomeric carbon atom whichoptionally may be etherified or acylated is that carbon atom at the1-position of the compound of Formula 13, said carbon atom bearing anether derivative.)

The glycoside halides (of which compound 16 is representative) may beprepared by standard techniques starting with an appropriately hydroxyprotected glycoside bearing one free hydroxy group. In these instancesthe alcohol is converted to its aldehyde by a Swern oxidation (treatmentwith oxalyl chloride in dimethylsulfoxide and triethylamine) followed byan insitu conversion of the aldehyde to an olefin by a Wittig reaction(going through a "ylide" prepared from methyltriphenylphosphoniumbromide using one equivalent each of n-butyllithium, potassiumt-butoxide and t-butanol in tetrahydrofuran at room temperature forabout 4 to 8 hours). The olefin is converted to its correspondingalcohol by hydroboration (treatment with borondimethylsulfide, undernitrogen, followed by oxidation with hydrogen peroxide and sodiumhydroxide). The alcohol is mesylated (treatment with mesyl chloride inCH₂ Cl₂ in excess NEt₃ at -15° C. to 0° C.) and the mesylate convertedto its halide (by treatment in ether at 0° C. with magnesium halide),preferably using the iodide.

The 1-deoxy-nojirimycin is prepared by reducing the correspondingδ-lactam of 2,3,6-tribenzyloxy-D-gluconic acid with borondimethylsulfide followed by treatment with. gaseous hydrochloric acid.

The following examples illustrate the processes and techniques suitablefor the preparation of the compounds of this invention.

EXAMPLE 1 Preparation of

1,5-DIDEOXY-4-O-(α,D-GLUCOPYRANOSYL)-1,5-(6-DEOXY-1-O-METHYL-6-.alpha.,D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

1,5-Dideoxy-4-O-(α,D-glucopyranosyl)-1,5-imino!-D-glucitol-1,5-dideoxy-4-O-(α,D-glucopyranosyl)-1,5-imino-D-glucitol Y. Ezure, Agric. Biol. Chem., 49, 2159, (1985)!(0.325 g ), 1 mmol ) and methyl 6-bromo-6-deoxy-α-D-glucopyranoside R.L. Whistler and A. K. M. Anisuzzaman, Methods Carbohydr. Chem., 8, 227,(1980)! (0.282 g, 1.1 mmol) are dissolved in dimethyl formamide (5 ml)and heated during 48 hours at 80° C. Dimethyl formamide is evaporatedunder high vacuum. The residue is taken with water and neutralized withamberlyst A26 OH.sup.⊖ form (3 g) and filtered. Water is evaporatedunder vacuum. Flash chromatography on silica gel and elution with a50:50:4 mixture of methanol, chloroform and water afforded the expectedcompound 1 ,5-dideoxy-4-O-(α,D-glucopyranosyl)-1,5-(6-deoxy-1-O-methyl-6-.alpha., D-glucopyranosyl)imino!-D-glucitol as anamorphous sol id (145 mg, 30%).

EXAMPLE 2 Preparation of

6-O-t-BUTYLDIMETHYLSILYL-1,5-DIDEOXY-1,5-(6-DEOXY-1-O-METHYL-6-α,D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

1,5-Dideoxy-1,5-(6-deoxy-1-O-methyl-6-α,D-glucopyranosyl)-imino!-D-glucitol EuropeanPatent Application EP 0 344 383 A1, published Dec. 6, 1989! (0.5 g, 1.47mmol) is dissolved in dry dimethyl formamide (5 ml). Imidazole (0.23 g,3.39 mmol) and t-butyldimethylchlorosilane (0.226 g, 1.5 mmol) areadded. The mixture is stirred 48 hours at room temperature. Dimethylformamide is evaporated under high vacuum. Flash chromatography onsilica gel and elution with methanol affords the expected product6-O-t-butyldimethylsilyl-1,5-dideoxy-1,5- (6-deoxy-1-O-methyl-6-α,D-glucopyranosyl)-imino! -D-glucitol as an amorphous solid (0.42 g,63%).

EXAMPLE 3 Preparation of

6-O-t-BUTYLDIMETHYLSILYL-2,3,4-TRI-O-BENZYL-1,5-DIDEOXY-(2,3,4-TRI-O-BENZYL-6-DEOXY-1-O-METHYL-6-α,D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

To a suspension of sodium hydride (0.140 g, 5.84 mmol) in dimethylformamide (20 ml) are added dropwise 6-O-t-butyldimethylsilyl-1,5-dideoxy-1,5-(6-deoxy-1-O-methyl-6-α,D-glucopyranosyl)imino!-D-glucitol (0.42 g,0.927 mmol), benzyl bromide (1 g, 5.84 mmol) and n-tetrabutyl ammoniumiodide (0.221 g, 0.6 mmol) in dimethyl formamide (30 ml). The mixture isstirred overnight and the resulting mixture is hydrolyzed with aqueousammonium chloride. Dimethyl formamide is evaporated under high vacuum.The residue is taken with water and extracted three times with ethylacetate. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure. Flash chromatography on silica geland elution with a 25:75 mixture of ethyl acetate and hexane affords6-O-t-butyl-dimethylsilyl-2,3-4-tri-O-benzyl-1,5-dideoxy-(2,3,4-tri-O-benzyl-6-deoxy-1-O-methyl-6-α,D-glucopyranosyl)imino!-D-glucitol(0.828 g, 90%) as an amorphous solid.

EXAMPLE 4 Preparation of

2,3,4-tri-O-BENZYL-1,5-DIDEOXY-(2,3,4-TRI-O-BENZYL-6-DEOXY-1-O-METHYL-6-.alpha.,D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

6-O-t-Butyldimethylsilyl-2,3,4-tri-O-benzyl-1,5-dideoxy-(2,3,4-tri-O-benzyl-6-deoxy-1-O-methyl-6-α,D-glucopyranosylimino!-D-glucitol(0.82 g, 0.825 mmol) is dissolved in tetrahydrofuran (10 ml)n-tetrabutyl ammonium fluoride trihydrate (0.39 g, 1.24 mmol) is addedand the mixture is stirred overnight at room temperature. The solvent isevaporated under reduced pressure. The residue is dissolved in ethylacetate and washed twice with water. The organic layer is dried oversodium sulfate and concentrated under reduced pressure. Flashchromatography on silica gel and elution with a 1:t mixture of hexaneand ethyl acetate affords 2,3,4-tri-O-benzyl-1,5-dideoxy(2,3,4-tri-O-benzyl-6-deoxy-1-O-methyl-6-.alpha.,D-glucopyranosyl)imino!-D-glucitolas an amorphous solid (0.71 g, 8%).

EXAMPLE 5 Preparation of

1,5-DIDEOXY-2,3,4-TRI-O-BENZYL-6-O-(6-O-TRIMETHYLSILYL-2,3,4-TRI-O-BENZYL-.alpha.,D-GLUCOPYRANOSYL-1,5(6-DEOXY-2,3,4-TRI-O-BENZYL-1-O-METHYL-6-.alpha.,D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

To a solution of2,3,4-tri-O-benzyl-6-O-trimethylsilyl-α,D-glucopyranosyl bromide C. P.Fei and T. H. Chan, Tetrahedron Letters, 28, 849, (1987)! (0.43 g, 0.74mmol) in ethanol-free chloroform (3 ml) is added diisopropylethylamine(0.5 ml ) and 2,3, 4-tri-O-benzyl-1,5-dideoxy(2,3,4-tri-O-benzyl-6-deoxy -1-O-methyl-6-α,D-glucopyranosyl)-imino!-D-glucitol (0.65 g, 0.74 mmol) in ethanol-freechloroform (3 ml). The mixture is stirred at room temperature during 24hours. The mixture is diluted with methylene chloride washed with water.The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford an amorphous solid. Flashchromatography on silica gel and elution with a 6:4 mixture of hexaneand ethyl acetate affords1,5-dideoxy-2,3,4-tri-O-benzyl-6-O-(6-O-trimethylsilyl-2,3,4-tri-O-benzyl-α,D-glucopyranosyl)-1,5- (6-deoxy-2,3,4-tri-O-benzyl-1-O-methyl-6-α,D-glucopyranosyl)imino!-D -glucitol as an anomorphous whitesolid (0.307 g, 30%).

EXAMPLE 6 Preparation of

1,5-DIDEOXY-6-O-(α,D-GLUCOPYRANOSYL)-1,5-(6-DEOXY-1-O-METHYL-6-.alpha.,D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

1,5-dideoxy-2,3,4-tri-O-benzyl-6-O-(6-O-trimethylsilyl-2,3,4-tri-O-benzyl-1-O-methyl-6-α,D-glucopyranosyl)-1,5-(6-deoxy-2,3,4-tri-O-benzyl-1-O-methyl-6-α,D-glucopyranosyl)imino!-D-glucitol(0.3 g, 0.217 mmol) is dissolved in acetic acid (40 ml). Palladium 10%on charcoal (0.6 g) is added. The mixture is hydrogenated during 7 daysat 3 atmosphere. The catalyst is removed by filtration and the solventsare evaporated under reduced pressure. The residue is dissolved in waterand passed through a column of Amberlyst A26 OH.sup.⊖. Water isevaporated under reduced pressure and flash chromatography on silica geland elution with a graded mixture of chloroform, methanol and wateraffords the expected amine 1,5-dideoxy-6-O-(α,D-glucopyranosyl)-1,5-(6-deoxy-1-O-methyl-6-.alpha.,D -glucopyranosyl)imino!-D-glucitol (0.85g, 79%) as an amorphous solid.

EXAMPLE 7 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-IMINO-D-GLUCITOL

To a solution of 2,3,6-tri-O-benzyl-5-deoxy-D-gluconic acid δ-lactam(compound described in Examples 64 to 69) (0.75 g, 1.6 mmol) in drytetrahydrofuran (15 ml) was added a 10 M solution of borane in methylsulfide (0.58 ml) under nitrogen at 0° C. The mixture was stirred 15 minat 0° C., 30 min at room temperature, then refluxed during 6 h andfinally stirred overnight at room temperature. The mixture was cooled to0° C. and the excess of borane was destroyed with methanol and stirred 1h at room temperature. The reaction mixture was treated with gaseoushydrochloric acid and refluxed during 1 h. The solvents were evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate andwashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford an oil. Flash chromatography on silicagel and elution with ethyl acetate afforded2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol which crystallizedin methanol (0.655 g, 90%); m.p. 73°-74° C.

EXAMPLE 8 Preparation of

METHYL2,3,4-TRI-O-BENZYL-6-O-TRIFLUOROMETHYLSULFONYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml)cooled to -15° C. was added trifluoromethanesulfonic anhydride (0.87ml). The mixture was stirred during 15 min at -10° C. then methyl2,3,4-tri-O-benzyl-α-D-glucopyranoside (1.2 g, 2.58 mmol) in methylenechloride (5 ml) was added (P. Kovac, V. Sklenar and C. Glaudemans,Carbohydr. Res., 175, 201 (1988)). The mixture was stirred during 1.5 hat -10° C. The reaction mixture was washed with water. The organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure to afford an oil. Flash chromatography on silica gel andelution with a 7:3 mixture of hexane and ethyl acetate afforded theexpected compound methyl2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-α-D-glucopyranoside whichwas crystallized from hexane (1.43 g, 93%); m.p. 44°-45° C.

EXAMPLE 9 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-(2,3,4-TRI-O-BENZYL-6-DEOXY-1-O-METHYL-6-α-D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

A solution of methyl2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-α-D-glucopyranoside (0.7g, 1.17 mmol) and 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol(0.509 g, 1.17 mmol). in ethanol-free chloroform (55 ml) was refluxedunder nitrogen during 48 h. The mixture was diluted in methylenechloride and washed successively with a saturated aqueous solution ofsodium bicarbonate and saturated brine. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford an oil. Flash chromatography on silica gel and elution with a 6:4mixture of hexane and ethyl acetate afforded the expected compound 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,4-tri-O-benzyl-6-deoxy-1-O-methyl-6-α-D-glucopyranosyl)imino!-D-glucitolwhich was crystallized from methanol (0.772 g, 75%); m.p. 102°-103° C.

EXAMPLE 10 Preparation of

1,5-DIDEOXY-1,5-(6-DEOXY-1-O-METHYL-6-α-D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,4-tri-O-benzyl-6-deoxy-1-O-methyl-6-α-D-glucopyranosyl)imino!-D-glucitol (0.646 g, 0.73 mmol) was dissolved inmethanol (20 ml), cyclohexene (10 ml) and Palladium hydroxide 20% oncharcoal (1.2 g) were added. The mixture was degased and refluxed 24 hunder argon atmosphere. The catalyst was filtered and washed twice withmethanol. The solvents were evaporated under reduced pressure. Theresidue was dissolved in water, the aqueous phase was extracted twicewith ethyl acetate. The aqueous layer was put to dryness under reducedpressure to afford a foam. Flash chromatography on silica gel andelution with a 50:50:4 mixture of methanol, chloroform and waterafforded the expected compound 1,5-dideoxy-1,5-(6-deoxy-1-O-methyl-6-α-D-glucopyranosyl)imino!-D-glucitol as a foam(0.13 g, 52%).

EXAMPLE 11 Preparation of

METHYL 2,3,4-TRI-O-BENZYL-6,7-DIDEOXY-α-D-GLUCOHEPT-6-ENOPYRANOSIDE

To a solution of oxalyl chloride (1.05 ml, 17.22 mmol) in drytetrahydrofuran (40 ml) cooled to -78° C., dry dimethyl sulfoxide (1.3ml, 18.04 mmol) was added dropwise and then stirred during 35 min at-35° C. The reaction mixture was cooled again to -78° C. and methyl2,3,4-tri-O-benzyl-α-D-glucopyranoside (6 g, 16.4 mmol) dissolved intetrahydrofuran (20 ml) was added and the mixture was stirred during 15min at -35° C., then triethylamine (11.5 ml, 82.65 mmol) was added andthe mixture was stirred during 1 h at -35° C. This aldehyde was usedwithout purification and isolation in a Wittig reaction described asfollows. To dried triphenylmethylphosphonium bromide (11.7 g, 32.8 mmol)suspended in tetrahydrofuran (700 ml) was added dropwise at -78° C. a1.42 M solution of n-butyllithium in hexane (23 ml, 32.66 mmol). Thereaction mixture was warmed to room temperature and stirred during 1.5h. Then the mixture was cooled to 0° C. and potassium tertio-butylate(3.68 g, 32.8 mmol) and dry tertio-butyl alcohol (3ml, 31.8 mmol) wereadded. The mixture was stirred again at room temperature during 30 min.The reaction mixture was cooled to -78° C. and the tetrahydrofuransolution of the aldehyde prepared above was added dropwise. The reactionmixture was warmed to room temperature and stirred during 2 h. Asaturated aqueous solution of ammonium chloride and the solvents wereevaporated under reduced pressure. The residue was dissolved in etherand washed with water. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to afford a brown oil.Flash chromatography on silica gel and elution with a 4:96 mixture ofethyl acetate and toluene afforded the expected olefin methyl2,3,4-tri-O-benzyl-6,7-dideoxy-α-D-glucohept-6-enopyranoside (3.26 g,55%) which crystallized from hexane; m.p. 46°-47° C.

EXAMPLE 12 Preparation of

METHYL 2,3,4-TRI-O-BENZYL-6-DEOXY-α-D-GLUCOHEPTOPYRANOSIDE

To a solution of methyl2,3,4-tri-O-benzyl-6,7-dideoxy-α-D-glucohept-6-enopyranoside (0.878 g,2.43 mmol) in dry tetrahydrofuran (5 ml) was added a 10 M solution ofborane in methyl sulfide (0.24 ml, 2.4 mmol) at 0° C. under nitrogen.The mixture was stirred during 3 h at room temperature. The excess ofborane was destroyed with ethanol (1 ml). The mixture was cooled at 0°C. 30% hydrogen peroxide (0.3 ml) were added. The mixture was refluxedduring 2 h. The reaction mixture was diluted with water and extractedthree times with ether. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to afford an oil. FlashChromatography on silica gel and elution with a 1:1 mixture of ethylacetate and hexane afforded the expected alcohol methyl2,3,4-tri-O-benzyl-6-deoxy-α-D-glucoheptopranoside (0.414 g, 45%) whichcrystallized from hexane; m.p. 50°-53° C.

EXAMPLE 13 Preparation of

METHYL2,3,4-TRI-O-BENZYL-6-DEOXY-7-O-METHYLSULFONYL-α-D-GLUCOHEPTOPYRANOSIDE

To a solution of methyl2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-α-D-glucoheptopyranoside(0.38 g, 0.83 mmol) in dry methylene chloride (10 ml) was addedtriethylamine (0.2 ml, 1.43 mmol). Then the solution was cooled to -10°C. and mesylchloride (0.08 ml), 1 mmol) was added. The mixture wasstirred an additional 15 min at -10° C., then the reaction was allowedto warm up to room temperature. The mixture was washed three times withwater. The organic phase was dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford a yellow oil. Flashchromatography on silica gel and elution with a 40:60 mixture of ethylacetate and hexane afforded the expected mesylate methyl2,3,4-tri-O-benzyl-6-deoxy-7-O-methyl-sulfonyl-α-D-glucoheptopyranosideas an oil (0.38 g, 91%).

EXAMPLE 14 Preparation of

METHYL 2,3,4-TRI-O-BENZYL-6,7-DIDEOXY-7-IODO-α-D-GLUCOHEPTO-PYRANOSIDE

To a solution of methyl2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-α-D-glucoheptopyranoside(0.38 g, 0.83 mmol) in ether (5 ml) was added at 0° C. a 0.375 Msolution of magnesium iodide (6.7 ml). The mixture was stirred 15 min at0° C. The excess of magnesium iodide was hydrolyzed with water. Thereaction mixture was washed with sodium thiosulfate and Water. Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford an oil. Flash chromatography on silicagel and elution with a 2:8 mixture of ethyl acetate and hexane affordedthe expected iodide methyl2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranoside which wascrystallized from hexane (0.368 g, 91%); m.p. 66°-68° C.

EXAMPLE 15 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-(2,3,4-TRI-O-BENZYL-6,7-DIDEOXY-1-O-METHYL-7-α-D-GLUCOHEPTOPYRANOSYL)IMINO!-D-GLUCITOL

A solution of methyl2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranoside (0.338 g,0.69 mmol) and 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.1g, 0.23 mmol) in dry dimethlylformamide (3 ml) was heated at 80° C.overnight along with dry potassium carbonate (0.127 g, 0.92 mmol). Thedimethyl formamide was evaporated under reduced pressure. The residuewas taken with ethyl acetate and washed twice with water. The organiclayer was dried over sodium-sulfate, filtered and concentrated underreduced pressure to afford an oil. Chromatography on neutral aluminumoxide activity III and elution with a 8:2 mixture of hexane and ethylacetate afforded the expected amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,4-tri-O-benzyl-6,7-dideoxy-1-O-methyl-7-α-D-glucoheptopyranosyl)imino!-D-glucitolwhich was crystallized in methanol (0.125 g, 60%); m.p. 42°-43° C.

EXAMPLE 16 Preparation of

1,5-DIDEOXY-1,5-(6,7-DIDEOXY-1-O-METHYL-7-α-D-GLUCOHEPTOPYRANOSYL)IMINO!-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,4-tri-O-benzyl-6,7-dideoxyl-1-O-methyl-7-α-D-glucoheptopyranosyl)imino!-D-glucitol(0.1 g, 0.11 mmol) was dissolved in methanol (10 ml) containing ethylacetate (0.1 ml) and water (1 ml). Palladium hydroxyde 20% on charcoal(0.05 g) was added. The mixture was hydrogenated at 1 atmosphere duringtwo weeks. The catalyst was removed filtration and the solvents wereevaporated under reduced pressure. Crystallization of the residue fromisopropanol afforded the expected amine 1,5-dideoxy-1,5-(6,7-dideoxy-1-O-methyl-7-α-D-glucoheptopyranosyl)imino!-D-glucitol(0.023 g, 58%).

EXAMPLE 17 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-(1-DEOXY-2,3:4,5-DI-O-ISOPROPYLIDENE-.beta.-D-FRUCTOPYRANOSYL)IMINO!-D-GLUCITOL

A solution of2,3:4,5-di-O-isopropylidene-1-O-trifluoromethylsulfonyl-8-D-fructopyranose(1.20 g, 3.06 mmol) (P. J. Card and W. D. Hitz, J. Amer. Chem. Soc.,106, 5348 (1984)) and1,5-dideoxy-2,3,6,-tri-O-benzyl-1,5-imino-D-glucitol (1,331 g, 3.06mmol) in ethanol-free chloroform (70 ml) is refluxed under nitrogenduring 60h. The mixture is diluted with methylene chloride and washedsuccessively with a saturated aqueous solution bicarbonate and saturatedbrine. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford an oil. Flashchromatography on silica gel and elution with graded mixture of hexaneand ethyl acetate will afford the expected amine 2,3,6-tri-O-benzyl-1,5-(1-deoxy-2,3:4,5-di-O-isopropylidene-β-D-fructopyranosyl)imino!-D-glucitol as an oil.

EXAMPLE 18 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-(1-DEOXY-2-O-METHYL-α-D-FRUCTOFURANOSYL)IMINO-1-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(1-deoxy-2,3:4,5-di-O-isopropylidene-.beta.-D-fructopyranosyl)imino!-D-glucitol(1.4 g, 2,074 mmol) is dissolved in methanol (100 ml) containing 2% ofdry hydrochloric acid. The mixture is refluxed during 48 h. The mixtureis neutralized with Amberlyst A 26 OH⁻⁻ form and filtered. The solventsare evaporated under reduced pressure. Flash chromatography on silicagel and elution with graded mixture of ethyl acetate and methanol willafford the expected amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(1-deoxy-2-O-methyl-α-D-fructofuranosyl)-imino!-D-glucitol.

EXAMPLE 19 Preparation of

1,5-DIDEOXY-1,5-(1-DEOXY-2-O-METHYL-α-D-FRUCTOFURANOSYL)IMINO!-D-GLUCITOL

The amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(1-deoxy-2-O-methyl-α-D-fructofuranosyl)imino!-D-glucitol (0.617 g,1.014 mmol) is dissolved in methanol (25 ml) containing water (2.5 ml),palladium hydroxide 20% on charcoal (0.3 g) is added. The mixture ishydrogenated during 4 days at atmospheric pressure. The catalyst isremoved by filtration and the solvents are evaporated under reducedpressure. Flash chromatography on silica gel and elution with gradedmixture of chloroform, methanol and water will afford the expected amine1,5-dideoxy-1,5- (deoxy-2-O-methyl-α-D-fructofuranosyl)imino!-D-glucitolas an amorphous solid.

EXAMPLE 20 Preparation of

METHYL2,3,6-TRI-O-BENZYL-4-O-TRIFLUOROMETHYLSULFONYL-α-D-GALACTOPYRANOSIDE

To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml)cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.87ml). The mixture is stirred during 15 min at -10° C., then methyl2,3,6-tri-O-benzyl-α-D-galacto-pyranoside (1.2 g, 2.58 mmol) inmethylene chloride (5 ml) is added (N. Morishima, S. Koto, M. Oshima, A.Sugimoto and S. Zen, Bull. Chem. Soc. Jpn., 56, 2849 (1983)). Themixture is washed with water. The organic layer is dried over sodiumsulfate, filtered and concentrated under reduced pressure so as toafford an oil which is the expected trillate methyl2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D-galactopyranoside.

EXAMPLE 21 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-(2,3,6-TRI-O-BENZYL-4-DEOXY-1-O-METHYL-4-α-D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

A solution of methyl2,3,6-tri-O-benzyl-4-O-trifluoro-methyfulfonyl-α-D-galactopyranoside(1.25 g, 2.53 mmol) and2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (1.098 g, 2.53 mmol)in ethanol-free chloroform (70 ml) is refluxed under nitrogen during 3days. The mixture is diluted with methylene chloride and washedsuccessively with a saturated aqueous solution of sodium bicarbonate andsaturated brine. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford an oil.Flash chromatography on silica gel and elution with graded mixture ofhexane and ethyl acetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,6-tri-O-benzyl-4-deoxy-1-O-methyl-4-α-D-glucopyranosyl)imino!-D-glucitol as an oil.

EXAMPLE 22 Preparation of

1,5-DIDEOXY-1,5-(4-DEOXY-1-O-METHYL-4-α-D-GLUCOPYRANOSYL)IMINO!-D-GLUCITOL

The amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,6-tri-O-benzyl-4-deoxy-1-O-methyl-α-D-glucopyranosyl)imino!-D-glucitol (0.911 g, 1.03 mmol) is dissolvedin methanol (20 ml). Cyclohexene (10 ml) and palladium hydroxide 20% oncharcoal are added. The mixture is degased and refluxed 16 h under argonatmosphere. The catalyst is filtered and washed twice with methanol. Thesolvents are evaporated under reduced pressure. The residue is dissolvedin water. The aqueous phase is extracted twice with ethyl acetate. Theaqueous layer is put to dryness under reduced pressure so as to afford afoam. Flash chromatography on silica gel and elution with a 50:50:4mixture of methanol, chloroform and water will afford the expected amine1,5-dideoxy-1,5-(4-deoxy-1-O-methyl-4-α-D-glucopyranosyl)imino!-D-glucitol as a foam.

EXAMPLE 23 Preparation of

METHYL2,3,4-TRI-O-BENZYL-6-O-(2,3,4-TRI-O-BENZYL-6-O-TRI-FLUOROMETHYLSULFONYL-.alpha.-D-GLUCOPYRANOSYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.24 ml) in methylene chloride (25 ml)cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.45ml). The mixture is stirred during 15 min at -10° C., then methyl6-O-(2,3,4-tri-O-benzyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-.alpha.-D-glucopyranoside 91.2 g, 1.34 mmol) in methylene chloride (5ml) is added (R. Eby and C. Schuerch, Carbohydr. Res., 50, 203 (1976)).The mixture is stirred during 1.5 h at -10° C. The reaction mixture iswashed with water. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford an oil(1.35 g, 98%) which will be the expected trillatemethyl-2,3,4-tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-α-D-glucopyranosyl)-α-D-glucopyranoside.

EXAMPLE 24 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-N-2,3,4-TRI-O-BENZYL-6-DEOXY-1-(2,3,4-TRI-O-BENZYL-1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-α-D-GLUCOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

A solution of methyl2,3,4-tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-.alpha.-D-glucopyranosyl)-α-D-glucopyranoside (1.35 g, 1.31 mmol) and2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.567 g, 1.31 mmol)in ethanol-free chloroform (50 ml ) is refluxed under nitrogen during 48h. The mixture is diluted with methylene chloride and washedsuccessively with a saturated aqueous solution of sodium bicarbonate andsaturated brine. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford a foam.Flash chromatography on silica gel and elution with graded mixture ofhexane and ethyl acetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,4-tri-O-benzyl-6-deoxy-1-(2,3,4-tri-O-benzyl-1-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitolas a foam.

EXAMPLE 25 Preparation of

1,5-DIDEOXY-N-6-DEOXY-1-(1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-α-D-GLUCOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

The amine 2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,4-tri-O-benzyl-6-deoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol(1.2 g, 0.915 mmol) is dissolved in methanol (30 ml). Palladiumhydrdxyde 20% on charcoal (0.5 g) is added. The mixture is hydrogenatedduring 4 days at 3 atmosphere. The catalyst is removed by,filtration andthe solvents are evaporated under reduced pressure. Flash chromatographyon silica gel and elution with graded mixture of chloroform, methanoland water will afford the expected amine 1,5-dideoxy-N-6-deoxy-1-(1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol as afoam.

EXAMPLE 26 Preparation of

METHYL6-O-(2,3,4-TRI-O-BENZYL-6,7-DIDEOXY-α-D-GLUCOHEPT-6-ENOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of oxalyl chloride (0.37 ml, 5.97 mmol) in drytetrahydrofuran (40 ml) cooled to -78° C., dry dimethyl sulfoxide (0.45ml, 6.26 mmol) is added dropwise and then stirred during 35 min at -35°C. The reaction mixture is cooled again to -78° C. and methyl6-O-(2,3,4-tri-O--benzyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (5.1g, 5.69 mmol) dissolved in tetrahydrofuran (20 ml) is added and themixture is stirred during 15 min at -35° C., then triethylamine (3.96ml, 28.45 mmol) is added and the mixture is stirred during 1 h at -35°C. This aldehyde is to be used without purification and isolation in aWittig reaction described as follows. To driedtriphenylmethylphosphonium bromide (4.059 g, 11.38 mmol) suspended intetrahydrofuran (100 ml) is added dropwise at -78° C. a 1.55 M solutionof n-butyllithium in hexane (7.34 ml, 11.38 mmol). The reaction mixtureis warmed to room temperature and stirred during 1.5 h. Then the mixtureis cooled to 0° C. and potassium tertio-butylate (1.275 g, 11.38 mmol)and dry tertio-butyl alcohol (1.04 ml, 11.38 mmol) are added. Themixture is stirred again at room temperature during 30 min. The reactionmixture is cooled to -78° C. and the tetrahydrofuran solution of thealdehyde prepared above is added dropwise. The reaction mixture iswarmed to room temperature and stirred during 2 h. A saturated aqueoussolution of ammonium chloride and the solvents are evaporated underreduced pressure. The residue is dissolved in ethyl acetate and washedwith water. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford a brown oil. Flashchromatography on silica gel and elution with a graded mixture of carbontetrachloride and ethyl acetate will afford the expected olefin methyl6-O-(2,3,4-tri-O-benzyl-6,7-dideoxy-α-D-glucohept-6-enopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranosideas an amorphous solid.

EXAMPLE 27 Preparation of

METHYL6-O-(2,3,4-TRI-O-BENZYL-6-DEOXY-α-D-GLUCOHEPTOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of methyl6-O-(2,3,4-tri-O-benzyl-6,7-di-deoxy-α-D-glucohept-6-enopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside(2.54 g, 2.85 mmol) in dry tetrahydrofuran (10 ml) is added a 10 Msolution of borane in methyl sulfide (0.28 ml, 2.8 mmol) at 0° C. undernitrogen. The mixture is stirred during 3 h at room temperature. Thenthe mixture is cooled to 0° C. The excess of borane is destroyed withethanol (1 ml). The mixture is cooled at 0° C. 30% hydrogen peroxide(0.3 ml) and 3 N aqueous solution of sodium hydroxide (0.3 ml) are to beadded. The mixture is refluxed during 2 h. The reaction mixture isdiluted with water and extracted three times with ethyl acetate. Theorganic layer is dried over sodium sulfate, filtered and concentratedunder reduced pressure so as to afford a foam. Flash chromatography onsilica gel and elution with a graded mixture of carbon tetrachloride andethyl acetate will afford the expected alcohol methyl6-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucoheptopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside as a foam.

EXAMPLE 28 Preparation of

METHYL6-O-(2,3,4-TRI-O-BENZYL-6,7-DIDEOXY-7-IODO-α-D-GLUCO-HEPTOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of methyl6-O-(2,3,4-tri-O-benzyl-6-deoxy-α-D-glucoheptopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside(1.245 g, 1.37 mmol) in dry methylene chloride (15 ml) is addedtriethylamine (0.29 ml, 2.05 mmol). Then the solution is cooled to -10°C., and mesylchloride (0.11 ml, 1.42 mmol) is added dropwise. Themixture is stirred an additional 15 min at -10° C., then the reactionmixture is washed three times with water. The organic layer is driedover sodium sulfate, filtered and concentrated under reduced pressure soas to afford a foam which is to be used without further purification.The crude methyl 6-O-(2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-α-D-glucoheptopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside isdissolved in ether (20 ml). To this mixture a 0.35 M solution ofmagnesium iodide in ether (17.5 ml) is added dropwise at 0° C. Theexcess of magnesium iodide is hydrolyzed with water. The reactionmixture is washed with sodium thiosulfate and water. The organic layeris dried over sodium sulfate, filtered and concentrated under reducedpressure to afford a foam. Flash chromatography on silica gel andelution with a graded mixture of carbon tetrachloride and ethyl acetatewill afford the expected iodide methyl6-O-(2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside as a foam.

EXAMPLE 29 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-N--2,3,4-TRI-O-BENZYL-6,7-DIDEOXY-1-(2,3,4-TRI-O-BENZYL-1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-7-α-D-GLUCOHEPTOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

A solution of the iodide methyl6-O-(2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside(1.145 g, 1.122 mmol) and the amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.162 g, 0.374 mmol ) in drydimethylformamide (4 ml) is heated at 80° C. over night along with drypotassium carbonate (0.206 g, 1.49 mmol ). The dimethylformamide isevaporated under reduced pressure. The residue is taken with ethylacetate and washed twice with water. The organic layer is dried oversodium sulfate, filtered and concentrated under reduced pressure so asto afford a foam. Chromatography on neutral aluminum oxide activity IIIand elution with a graded mixture of carbon tetrachloride and ethylacetate will afford the expected amine 2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,4-tri-O-benzyl-6,7-dideoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-7-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitolas a foam.

EXAMPLE 30 Preparation of

1,5-DIDEOXY-N-6,7-DIDEOXY-1-(1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-7-.alpha.-D-GLUCOHEPTOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

The amine 2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,4-tri-O-benzyl-6,7-dideoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitol(0.337 g, 0.254 mmol) is dissolved in methanol (30 ml). Palladiumhydroxide 20% on charcoal (0.4 g) is added. The mixture is hydrogenatedduring 4 days at 3 atmospheres. The catalyst is removed by filtrationand the solvents are evaporated under reduced pressure. Flashchromatography on silica gel and elution with a graded mixture ofchloroform, methanol and water will afford the expected amine1,5-dideoxy-N- 6,7-dideoxy-l-(1-O-methyl-6-O--α-D-glucopyranosyl)-7-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitol as an amorphous solid.

EXAMPLE 31 Preparation of

METHYL 2,3,6-TRI-O-BENZYL-4-CYANO-4-DEOXY-α-D-GLUCOPYRANOSIDE

A solution of methyl2,3,6-tri-O-benzyl-4-O-trifluoromethylsulfonyl-α-D-galactopyranoside (3g, 6.07 mmol) and tetra-n-butyl ammonium cyanide (6.51 g, 24.28 mmol) inethanol-free chloroform (60 ml) is refluxed under nitrogen during 24 h.The reaction mixture is diluted with methylene chloride, washed twicewith water. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford an oil. Flashchromatography on silica gel and elution with a graded mixture of hexaneand ethyl acetate will afford the expected nitrile methyl2,3,6-tri-O-benzyl-4-cyano-4-deoxy-α-D-glucopyranoside as an oil.

EXAMPLE 32 Preparation of

METHYL 2,3,6-TRI-O-BENZYL-4-DEOXY-4-FORMYL-α-D-GLUCOPYRANOSIDE

To a solution of methyl2,3,6-tri-O-benzyl-4-cyano-4-deoxy-α-D-glucopyranoside (1.75 g, 3.7mmol) in dry tetrahydrofuran (10 ml) is added dropwise at -78° C. a 1.2M solution of diisobutyl aluminum hydride in n-hexane (3.1 ml). Themixture is stirred under argon at -78° C. during 3 h. Methanol (2 ml) isadded and the mixture is warmed to 0° C. Then the solvents areevaporated under reduced pressure. Ether (50 ml) and 0.1 N aqueoushydrochloric acid (40 ml) are added, the mixture is stirred at 0° C.during 1 h. Then after decantation the organic layer is dried oversodium sulfate, filtered and concentrated under reduced pressure so asto afford the expected aldehyde methyl2,3,6-tri-O-benzyl-4-deoxy-4-formyl-α-D-glucopyranoside as an oil whichis used without purification.

EXAMPLE 33 Preparation of

METHYL 2,3,6-TRI-O-BENZYL-4-DEOXY-4-HYDROXYMETHYL-α-D-GLUCO-PYRANOSIDE

The aldehyde methyl2,3,6-tri-O-benzyl-4-deoxy-4-formyl-α-D-glucopyranoside (1.7 g, 3.57mmol) is dissolved in ethanol (15 ml). The mixture is cooled to 0° C.and solid sodium borohydride (0.068 g, 1.8 mmol) is added portionwise.The mixture is stirred 1 h at 0° C. Then acetic acid (0.4 ml) is addedand the solvents are evaporated under reduced pressure. The residue istaken up with ethyl acetate and washed with saturated aqueous sodiumbicarbonate and saturated brine. The organic layer is dried over sodiumsulfate, filtered and concentrated under reduced pressure so as toafford an oil. Flash chromatography over silica gel and elution with agraded mixture of hexane and ethyl acetate will afford the expectedalcohol methyl2,3,6-tri-O-benzyl-4-deoxy-4-hydroxy-methyl-α-D-glucopyranoside as anoil.

EXAMPLE 34 Preparation of

METHYL2,3,6-TRI-O-BENZYL-4-DEOXY-4-TRIFLUOROMETHYL-SULFONYLOXYMETHYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.45 ml) in methylene chloride (30 ml)cooled to -15° C. is added trifluoromethanesulfonic anhydride (0.84 ml).The mixture is stirred during 15 min at -10° C., then methyl2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranoside (1.19 g,2.49 mmol) in methylene chloride (5 ml) is added. The mixture is stirredduring 1.5 h at -10° C. The reaction mixture is washed with water. Theorganic layer is dried over sodium sulfate, filtered and concentratedunder reduced pressure so as to afford an oil which is the expectedtrillate methyl2,3,6-tri-O-benzyl-4-deoxy-4-trifluoromethylsulfonyloxymethyl-α-D-glucopyranoside.

EXAMPLE 35 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-(2,3,6-TRI-O-BENZYL-4-DEOXY-1-O-METHYL-4-α-D-GLUCOPYRANOSYL)METHYLIMINO!-D-GLUCITOL

A solution of methyl2,3,6-tri-O-benzyl-4-deoxy-4-tri-fluoromethylsulfonyloxymethyl-α-D-glucopyranoside(1 g, 1.64 mmol) and 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol(0.71 g, 1.64 mmol) in ethanol-free chloroform (60 ml) is refluxed undernitrogen during 48 h. The mixture is diluted in methylene chloride andwashed successively with a saturated aqueous solution of sodiumbicarbonate and saturated brine. The organic layer is dried over sodiumsulfate, filtered and concentrated under reduced pressure so as toafford a foam. Flash chromatography on silica gel and elution with agraded mixture of hexane and ethyl acetate will afford the expectedamine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,6-tri-O-benzyl-4-deoxy-1-O-methyl-4-α-D-glucopyranosyl)-methylimino!-D-glucitol as a foam.

EXAMPLE 36 Preparation of

1,5-DIDEOXY-1,5-(4-DEOXY-1-O-METHYL-4-α-D-GLUCOPYRANOSYL)METHYLIMINO!-D-GLUCITOL

The amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-(2,3,6-tri-O-benzyl-4-deoxy-1-O-methyl-4-α-D-glucopyranosyl)methylimino!-D-glucitol (0.98 g, 1.09 mmol) is dissolvedin methanol (20 ml). Cyclohexene (10 ml) and palladium hydroxide 20% oncharcoal (0.8 g) are added and the mixture is refluxed under nitrogenduring 8 h. The catalyst is removed by filtration and the solvents areevaporated under reduced pressure. Flash chromatography on silica geland elution with a graded mixture of chloroform, methanol and water willafford the expected amine 1,5-dideoxy-1,5-(4-deoxy-1-O-methyl-4-α-D-glucopyranosyl)methylimino!-D-glucitol as anamorphous solid.

EXAMPLE 37 Preparation of

2,3,6-TRI-O-BENZYL-D-GALACTOPYRANOSE

Methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (5 g, 10.775 mmol) isdissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water(50 ml) N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull.Chem. Soc. Jpn., 56, 2849 (1983)!. The mixture. is stirred overnight at0° C. The solvents are evaporated under reduced pressure withoutheating. The residue is dissolved in ethyl acetate and washedsuccessively with sodium bicarbonate and brine. The organic layer isdried over sodium sulfate, filtered and concentrated under reducedpressure so as to afford an oil. Flash chromatography on silica gel andelution with a graded mixture of ethyl acetate and hexane will afford2,3,6-tri-O-benzyl-D-galactopyranose as an oil.

EXAMPLE 38 Preparation of

1,4-DI-O-ACETYL-2,3,6-TRI-O-BENZYL-D-GALACTOPYRANOSE

2,3,6-tri-O-benzyl-D-galactopyranose (3.927 g, 8.72 mmol) is dissolvedin dry pyridine (25 ml) and acetic anhydride (5 ml) is added. Themixture is stirred during 24 h at room temperature. The solvent isevaporated under high vacuum. The residue is dissolved in ethyl acetateand washed with water. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford theexpected diacetate 1,4-di-O-acetyl-2,3,6-tri-O-benzyl-D-galactopyranose(4.64 g, 99%) as an oil which can be used without purification.

EXAMPLE 39 Preparation of

4-O-ACETYL-2,3,6-TRI-O-BENZYL-α-D-GALACTOPYRANOSYL CHLORIDE

A solution of 1,4-di-O-acetyl-2,3,6-tri-O-benzyl-D-galactopyranose (4.64g, 8.67 mmol) in ether (10 ml) is treated with ethereal hydrogenchloride (0.2 g/ml, 25 ml). The mixture is stirred at room temperatureduring 48 h. The solvents are evaporated under reduced pressure so as toafford an oil. Flash chromatography on silica gel and elution with agraded mixture of carbon tetrachloride and ethyl acetate will afford4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride as an oil.

EXAMPLE 40 Preparation of

METHYL4-O-(4-O-ACETYL-2,3,6-TRI-O-BENZYL-α-D-GALACTOPYRANOSYL)-2,3,6-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

Ethereal silver perchlorate (0.08 M, 84.5 ml, 6.76 mmol) is added withstirring at -30° C. to a solution ofmethyl-2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.284 g, 4.93 mmol) (P.J. Garegg, H. Hultberg and S. Wallin, Carbohydr. Res., 108, 97 (1982)),4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride (3.142 g,6.154 mmol) and 2,4,6-trimethylpyridine (0.89 ml, 6.76 mmol) in ether(20 ml). The mixture is stirred 15 min at -30° C. and silver chlorideprecipitated. The mixture is filtered through a celite pad, the solidsare washed with ether, the filtrate is concentrated under reducedpressure. The residue is dissolved in methylene chloride and the organiclayer is washed successively with aqueous sodium thiosulfate and water.The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford a foam. Flashchromatography on silica gel and elution with a graded mixture of hexaneand ethyl acetate will afford methyl4-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as a foam.

EXAMPLE 41 Preparation of

METHYL2,3,6-TRI-O-BENZYL-4-O-(2,3,6-TRI-O-BENZYL-α-D-GALACTOPYRANOSYL)-.alpha.-D-GLUCOPYRANOSIDE

Methyl4-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside(2.543 g, 2.71 mmol) is dissolved in hot toluene (2 0 ml) and methanol(80 ml) is added, followed by a few drops of 1 M methanolic sodiummethoxide. The mixture is stirred at room temperature during 2 h. Thereaction mixture is made neutral with Amberlite IR 120 (H⁺) resin,filtered and concentrated under reduced pressure so as to afford methyl2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-.alpha.-D-glucopyranoside as an amorphous solid.

EXAMPLE 42 Preparation of

METHYL4-O-(2,6-TRI-O-BENZYL-4-O-TRIFLUOROMETHYLSULFONYL-α-D-GALACTOPYRANOSYL)-2,3,6-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.49 ml) in dry methylene chloride (40ml) cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.91ml). The mixture is stirred during 15 min at -10° C., then methyl2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D-glucopyranoside (2.428 g, 2.71 mmol) in methylenechloride (10 ml) is added. The mixture is stirred during 1.5 h at -10°C. The reaction mixture is washed with water. The organic layer is driedover sodium sulfate, filtered and concentrated under reduced pressure soas to afford an oil which will be the expected triflate methyl4-O-(2,3,6-tri-O-benzyl-4-O-tri-fluoromethylsulfonyl-α-D-galactopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside.

EXAMPLE 43 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-N- 2,3,6-TRI-O-BENZYL-4-DEOXY-1-(2,3,6-TRI-O-BENZYL-1-O-METHYL-4-O-α-D-GLUCOPYRANOSYL)-α-D-GLUCOPYRANOSYL!-1-5-IMINO-D-GLUCITOL

A solution of methyl4-O-(2,3,6-tri-O-benzyl-4-O-trifluoromethylsulfonyl-α-D-galactopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (1.52 g, 1.46 mmol) and2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.632 g, 1.46 mmol)in ethanol-free chloroform (50 ml) is refluxed under nitrogen during 48h. The mixture is diluted in methylene chloride and washed successivelywith a saturated aqueous solution of sodium bicarbonate and saturatedbrine. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford a foam. Flashchromatography on silica gel and elution with a graded mixture of hexaneand ethyl acetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,6-tri-O-benzyl-1-O-methyl-4-O-α-D-gluco-pyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitolas an amorphous solid.

EXAMPLE 44 Preparation of

1,5-DIDEOXY-N-4-DEOXY-1-(1-O-α-METHYL-4-O-α-D-GLUCOPYRANOSYL)-α-D-GLUCOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,6-tri-O-benzyl-1-O-methyl-4-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol (1 g,0.762 mmol) is dissolved in methanol (30 ml). Palladium hydroxide 20% oncharcoal (0.5 g) is added. The mixture is hydrogenated during 4 days at3 atmospheres. The catalyst is removed by filtration and the solventsare evaporated under reduced pressure. Flash chromatography on silicagel and elution with a graded mixture of chloroform, methanol and waterwill afford the expected amine 1,5-dideoxy-N-4-deoxy-1-(1-O-methyl-4-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitolas an amorphous solid.

EXAMPLE 45 Preparation of

1-ETHENYL-1,2:3,4-DI-O-ISOPROPYLIDENE-β-D-ARABINOPYRANOSE

To a solution of oxalyl chloride (1.05 ml, 17.22 mmol) in drytetrahydrofuran (40 ml) cooled to -78° C., dry dimethyl sulfoxide (1.3ml, 18.04 mmol) is added dropwise and then stirred during 35 min at -35°C. The reaction mixture is cooled again to -78° C. and2,3:4,5-di-O-isopropylidene-D-fructopyranose (4.26 g, 16.4 mmol) (R. F.Brady, Carbohydr. Res., 15, 35 (1970)) dissolved in tetrahydrofuran (20ml) is added and the mixture is stirred during 15 min at -35° C. thentriethylamine (11.5 ml, 82.65 mmol) is added and the mixture is stirredduring 1 h at -35° C. This aldehyde can be used without purification andisolation in a wittig reaction described as follows. To driedtriphenylmethylphosphonium bromide (11.7 g, 32.8 mmol) suspended intetrahydrofuran (400 ml) is added dropwise at -78° C. a 1.55 M solutionof n-butyllithium in hexane (21 ml, 32.66 mmol). The reaction mixture iswarmed to room temperature and stirred during 1.5 h. Then the mixture iscooled to 0° C. and potassium tertio-butylate (3.68 g, 32.8 mmol) anddry tertio-butyl alcohol (3 ml, 31.8 mmol) are added. The mixture isstirred again at room temperature during 30 min. The reaction mixture iscooled to -78° C. and the tetrahydrofuran solution of the aldehydeprepared above is added dropwise. The reaction mixture is warmed to roomtemperature and stirred during 2 h. A saturated aqueous solution ofammonium chloride and the solvents are evaporated under reducedpressure. The residue is dissolved in ether and washed with water. Theorganic layer is dried over sodium sulfate, filtered and concentratedunder reduced pressure so as to afford a brown oil. Flash chromatographyon silica gel and elution with a graded mixture of hexane and ethylacetate will afford the expected olefin1-ethenyl-1,2,3,4-di-O-isopropylidene-β-D-arabinopyranose as an oil.

EXAMPLE 46 Preparation of

1,2:3,4-DI-O-ISOPROPYLIDENE-1-(2-HYDROXYETHYL)-β-D-ARABINOPYRANOSE

To a solution of1-ethenyl-1,2:3,4-di-O-isopropylidene-β-D-arabinopyranose (2 g, 7.81mmol) in dry tetrahydrofuran (15 ml) is added a 10 M solution of boranein methyl sulfide (0.78 ml, 7.8 mmol) at 0° C. under nitrogen. Themixture is stirred during 3 h at room temperature. The excess of boraneis destroyed with ethanol (3 ml). The mixture is cooled at 0° C. 30%hydrogen peroxide (1 ml) and 3 N aqueous solution of sodium hydroxide (1ml) are added. The mixture is refluxed during 2 h. The reaction mixtureis diluted with water and extracted three times with ethyl acetate. Theorganic layer is dried over sodium sulfate, filtered and concentratedunder reduced pressure so as to afford an oil. Flash chromatography onsilica gel and elution with a 1:1 mixture of ethyl acetate and hexanewill afford the expected alcohol1,2:3,4-di-O-isopropylidene-1-(2-hydroxyethyl)-β-D-arabinopyranose as anoil.

EXAMPLE 47 Preparation of

1,2:3,4-DI-O-ISOPROPYLIDENE-1-(2-IODOETHYL)-α-D-ARABINOPYRANOSE

To a solution of1,2,3,4-di-O-isopropylidene-1-(2-hydroxyethyl)-α-D-arabinose (1.7 g, 6.2mmol) in dry methylene chloride (30 ml) is added triethylamine (1.3 ml,9.3 mmol). Then the mixture is cooled to -10° C. and mesylchloride (0.5ml, 6.46 mmol) is added dropwise. The mixture is stirred an additional15 min at -10° C., then the reaction is allowed to warm up to roomtemperature. The mixture is washed three times with water. The organicphase is dried over sodium sulfate, filtered and concentrated underreduced pressure so as to afford a yellow oil which can be used withoutpurification. The crude1,2,3,4-di-O-isopropylidene-1-(2-methylsulfohyloxyethyl)-α-D-arabinoseis dissolved in ether (15 ml). To this mixture a 0.35 M solution ofmagnesium iodide in ether (53 ml) is added at 0° C. The mixture isstirred 15 min at 0° C. The excess of magnesium iodide is hydrolyzedwith water. The reaction mixture is washed with aqueous sodiumthiosulfate and water. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford an oil.Flash chromatography on silica gel and elution with a 9:1 mixture ofhexane and ethyl acetate will afford the expected iodide1,2:3,4-di-O-isopropylidene-1-(2-iodoethyl)-β-D-arabinopyranose as aslightly yellow oil.

EXAMPLE 48 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-{2-(1,2,3,4-DI-O-ISOPROPYLIDENE-1-.beta.-D-ARABINOPYRANOSYL)ETHYL)IMINO)-D-GLUCITOL

A solution of 1,2:3,4-di-O-isopropylidene-1-(2-iodoethyl)-β-D-arabinose(1.9 g, 4.95 mmol) and2,3,6-tri-O--benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.714 g, 1.65mmol) in dry dimethylformamide (10 ml) is heated at 80° C. overnightalong with dry potassium carbonate (0.91 g, 6.6 mmol). Thedimethylformamide is evaporated under reduced pressure. The residue istaken with ethyl acetate and washed twice with water. The organic layeris dried over sodium sulfate, filtered and concentrated under reducedpressure so as to afford an oil. Chromatography on neutral aluminumoxide activity III and elution with a graded mixture of hexane and ethylacetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-1,5{2-(1,2,3,4-di-O-isopropylidene-1-.beta.-D-arabinopyranosyl)!imino}-D-glucitol as a foam.

EXAMPLE 49 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-1,5-{2-(1-O-METHYL-1-α-DARABINOFURANOSYL)ETHYL!IMINO}-D -GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-{2-(1,2:3,4-di-O-isopropylidene-1-.beta.-D-arabinopyranosyl)ethyl!imino}-D-glucitol (0.739 g, 1.072 mmol) is dissolved in methanol(60 ml) containing 5% of dry hydrochloric acid and is refluxed during 24h. The reaction mixture is cooled to room temperature and neutralizedwith Amberlyst A26 OH⁻⁻ form. The mixture is filtered and the solvent isevaporated under reduced pressure so as to give a foam. Flashchromatography on silica gel and elution with a graded mixture of ethylacetate and methanol will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-{2-(1-O-methyl-1-α-D-arabinofuranosyl)ethyl!-imino}-D-glucitol as a foam.

EXAMPLE 50 Preparation of

1,5-DIDEOXY-1,5-(2-(1-O-METHYL-1-α-D-ARABINOFURANOSYL)ETHYL!-IMINO)-D-GLUCITOL

The amine 2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-{2-(1-O-methyl-1-α-D-arabinofuranosyl)ethyl!imino}-D-glucitol (0.4 g,0.642 mmol) is dissolved in a 9:1 mixture of methanol and water (20 ml).Palladium hydroxide 20% on charcoal (0.2 g) is added and the mixture ishydrogenated during 4 days at atmospheric pressure. The catalyst isremoved by filtration and the solvents are evaporated under reducedpressure. Flash chromatography on silica gel and elution with a gradedmixture of chloroform, methanol and water will afford the expected amine1,5-dideoxy-1,5-(2-(1-O-methyl-1-α-D-arabinofuranosyl)ethyl!-imino}-D-glucitol as anamorphous solid.

EXAMPLE 51 Preparation of

METHYL6-O-(4-O-ACETYL-2,3,6-TRI-O-BENZYL-α-D-GALACTOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

Ethereal silver perchlorate (0.08 M, 76.9 ml, 6.15 mmol) is added Withstirring at -30° C. to a solution of methyl2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.078 g, 4.48 mmol),4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride (2,859 g,5.6 mmol) and 2,4,6-trimethylpyridine (0.81 ml, 6.15 mmol) in ether (20ml). The mixture is stirred 15 min at -30° C. and silver chlorideprecipitated. The mixture is filtered through a celite pad, the solidsare washed with ether, the filtrate is concentrated under reducedpressure. The residue is dissolved in methylene chloride and the organiclayer is washed successively with aqueous sodium thiosulfate and water.The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford a foam. Flashchromatography on silica gel and elution with a graded mixture of hexaneand ethyl acetate will afford methyl6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranosideas a foam.

EXAMPLE 52 Preparation of

METHYL2,3,4-TRI-O-BENZYL-6-O-(2,3,6-TRI-O-BENZYL-α-D-GALACTOPYRANOSYL)-.alpha.-D-GLUCOPYRANOSIDE

Methyl6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside(2.314 g, 2.46 mmol) is dissolved in hot toluene (20 ml) and methanol(80 ml) is added, followed by a few drops of 1 M methanolic sodiummethoxide. The mixture is stirred at room temperature during 2 h. Thereaction mixture is made neutral with Amberlite IR 120 (H⁺) resin,filtered and concentrated under reduced pressure so as to afford methyl2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-.alpha.-D-glucopyranoside as an amorphous solid.

EXAMPLE 53 Preparation of

METHYL6-O-(2,3,6-TRI-O-BENZYL-4-O-TRIFLUOROMETHYLSULFONYL-α-D-GALACTOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.45 ml) in dry methylene chloride (40ml) cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.83ml). The mixture is stirred during 15 min at -10° C., then methyl2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-α-D-galactopyranosyl)-α-D-glucopyranoside (2.21 g, 2.46 mmol) in methylenechloride (10 ml) is added. The mixture is washed with water. The organiclayer is dried over sodium sulfate, filtered and concentrated underreduced pressure so as to afford an oil which will be the expectedtrillate methyl6-O-(2,3,6-tri-O-benzyl-4-O-tri-fluoromethylsulfonyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside.

EXAMPLE 54 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-N-2,3,6-TRI-O-BENZYL-DEOXY-1-(2,3,4-TRI-O-BENZYL-1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-α-D-GLUCOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

A solution of methyl6-O-(2,3,6-tri-O-benzyl-4-O-trifluoromethylsulfonyl-α-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (1.6g, 1.55 mmol) and2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.671 g, 1.55 mmol)in ethanol-free chloroform (50 ml) is refluxed under nitrogen during 48h . The mixture is diluted in methylene chloride and washed successivelywith a saturated aqueous solution of sodium bicarbonate and saturatedbrine. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford a foam. Flashchromatography on silica gel and elution with a graded mixture of hexaneand ethyl acetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol as anamorphous solid.

EXAMPLE 55 Preparation of

1,5-DIDEOXY-N-4-DEOXY-1-(1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-α-D-GLUCOPYRANOSYL!-1,5-IMINO-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-N-2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol (1.2g, 0.915 mmol) is dissolved in methanol (30 ml). Palladium hydroxide 20%on charcoal (0.6 g) is added. The mixture is hydrogenated during 4 daysat 3 atmospheres. The catalyst is removed by filtration and the solventsare evaporated under reduced pressure. Flash chromatography on silicagel and elution with a graded mixture of chloroform, methanol and waterwill afford the expected amine 1,5-dideoxy-N-4-deoxy-1-(1-O-methyl-6-O-α-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol as an amorphous solid.

EXAMPLE 56 Preparation of

2,3,6-TRI-O-BENZYL-4-DEOXY-4-HYDROXYMETHYL-D-GLUCOPYRANOSE

Methyl 2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranoside(4.78 g, 10 mmol) is dissolved at 0° C. in a 9:1 mixture oftrifluoroacetic acid and water (50 ml). The mixture is stirred overnightat 0° C. The solvents are evaporated under reduced pressure withoutheating. The residue is dissolved in ethyl acetate and washedsuccessively with sodium bicarbonate and brine. The organic layer isdried over sodium sulfate, filtered and concentrated under reducedpressure so as to afford an oil. Flash chromatography on silica gel andelution with a graded mixture of ethyl acetate and hexane will afford2,3,6-tri-O-benzyl-4-deoxy-4-hydroxy-methyl-D-glucopyranose as an oil.

EXAMPLE 57 Preparation of

ACETYL 2,3,6-TRI-O-BENZYL-4-DEOXY-4-ACETYLOXYMETHYL-D-GLUCO-PYRANOSIDE

2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-D-glucopyranose (5.10 g, 9.30mmol) is dissolved in dry pyridine (25 ml) and acetic anhydride (5 ml)is added. The mixture is stirred during 24 h at room temperature. Thesolvent is evaporated under high vacuum. The residue is dissolved inethyl acetate and washed with water. The organic layer is dried oversodium sulfate, filtered and concentrated under reduced pressure so asto afford the expected diacetate acetyl2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-D-gluco-pyranoside as anoil which is used without purification.

EXAMPLE 58 Preparation of

2,3,6-TRI-O-BENZYL-1,4-DIDEOXY-4-ACETYLOXYMETHYL-D-GLUCOPYRANOSYLCHLORIDE

Acetyl 2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-D-glucopyranoside(5.10 g, 9.30 mmol) in ether (10 ml) is treated with ethereal hydrogenchloride (0.2 g/ml, 25 ml). The mixture is stirred at room temperatureduring 48 h. The solvents are evaporated under reduced pressure so as toafford an oil. Flash chromatography on silica gel and elution with agraded mixture of carbon tetrachloride and ethyl acetate will afford2,3,6-tri-O-benzyl-1,4-dideoxy-4-acetyloxymethyl-D-glucopyranosylchloride as an oil.

EXAMPLE 59 Preparation of

METHYL4-O-(2,3,6-TRI-O-BENZYL-4-DEOXY-4-ACETYLOXYMETHYL-α-D-GLUCOPYRANOSYL)-2,3,6-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

Ethereal silver perchlorate (0.08 M, 9.58 ml, 7.67 mmol) is added withstirring at -30° C. to a solution of methyl2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.592 g, 5.59 mmol),2,3,6-tri-O-benzyl-1,4-dideoxy-4-acetyloxymethyl-D-gluco-pyranosylchloride (3.661 g, 6.98 mmol) in ether (20 ml). The mixture is stirred15 min at -30° C. and silver chloride precipitated. The mixture isfiltered through a celite pad, the solids are washed with ether, thefiltrate is concentrated under reduced pressure. The residue isdissolved in methylene chloride and the organic layer is washedsuccessively with aqueous sodium thiosulfate and water. The organiclayer is dried over sodium sulfate, filtered and concentrated underreduced pressure so as to afford a foam. Flash chromatography on silicagel and elution with a graded mixture of hexane and ethyl acetate willafford methyl4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranosideas a foam.

EXAMPLE 60 Preparation of

METHYL4-O-(2,3,6-TRI-O-BENZYL-4-DEOXY-4-HYDROXYMETHYL-α-D-GLUCOPYRANOSYL)-2,3,6-TRI-D-BENZYL-α-D-GLUCOPYRANOSIDE

Methyl4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside(3.19 g, 3.35 mmol) is dissolved in hot toluene (20 ml) and methanol (80ml) is added, followed by a few drops of 1 M methanolic sodiummethoxide. The mixture is stirred at room temperature during 2 h. Thereaction mixture is made neutral with Amberlite IR 120 (H⁺) resin,filtered and concentrated under reduced pressure so as to afford methyl4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranosideas an amorphous solid.

EXAMPLE 61 Preparation of

METHYL4-O-(2,3,6-TRI-O-BENZYL-4-DEOXY-4-TRIFLUOROMETHYL-SULFONYLOXMETHYL-α-D-GLUCOPYRANOSYL)-2,3,6-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.6 ml) in dry methylene chloride (50 ml)cooled to -15° C. is added trifluoromethane sulfonic anhydride (1.12ml). The mixture is stirred during 15 min at -10° C., then methyl4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (3.049g, 3.35mmol) in methylene chloride (15 ml)is added. The mixture is washed withwater. The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford an oil which will bethe expected triflate methyl4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-trifluoromethyl-sulfonyloxymethyl-.alpha.-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside.

EXAMPLE 62 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-N-{2,3,6-TRI-O-BENZYL-4-DEOXY-1-(2,3,6-TRI-O-METHYL-4-O-α-D-GLUCOPYRANOSYL)-4-α-D-GLUCOPYRANOSYL!METHYL)-1,5-IMINO-D-GLUCITOL

A solution of methyl4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-trifluoromethylsulfonyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (1.82 g, 1.75 mmol) and2,3,6-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol (0.758 g, 1.75 mmol)in ethanol-free chloroform (50 ml) is refluxed under nitrogen during 48h. The mixture is diluted in methylene chloride and washed successivelywith a saturated brine. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford a foam.Flash chromatography on silica gel and elution with a graded mixture ofhexane and ethyl acetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-N-{2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,6-tri-O-benzyl-4-O-α-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}1,5-imino-D-glucitolas an amorphous solid.

EXAMPLE 63 Preparation of

1.5-DIDEOXY-N-{4-DEOXY-1-(1-O-METHYL-4-O-α-D-GLUCOPYRANOSYL)-4-.alpha.-D-GLUCOPYRANOSYL!METHYL}1,5-IMINO-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-N-(2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,6-tri-O-benzyl-1-O-methyl-4-O-α-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}1,5-imino-D-glucitol(1.3 g, 1.247 mmol) is dissolved in methanol (40 ml). Palladiumhydroxide 20% on charcoal (0.6 g) is added. The mixture is hydrogenatedduring 4 days at 3 atmospheres. The catalyst is removed by filtrationand the solvents are evaporated under reduced pressure. Flashchromatography on silica gel and elution with a graded mixture ofchloroform, methanol and water will afford the expected amine1,5-dideoxy-N-( 4-deoxy-1-(1-O-methyl-4-O-α-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}1,5-imino-D-glucitol as anamorphous solid.

EXAMPLE 64 Preparation of

METHYL6-O-(2,3,6-TRI-O-BENZYL-4-DEOXY-4-ACETYLOXYMETHYL-α-D-GLUCOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

Ethereal silver perchlorate (0.08 M, 76.7 ml, 6.13 mmol) is added withstirring at -30° C. to a solution of methyl2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.074 g, 4.472 mmol),2,3,6-tri-O-benzyl-1,4-dideoxy-4-acetyloxymethyl-D-gluco-pyranosylchloride (6.13 mmol) and 2,4,6trimethylpyridine (0.80 ml, 6.13 mmol) inether (20 ml). The mixture is stirred 15 min at -30° C. and silver.chloride precipitated. The mixture is filtered through a celite pad, thesolids are washed with ether, the filtrate is concentrated under reducedpressure. The residue is dissolved in methylene chloride and the organiclayer is washed successively with aqueous sodium thiosulfate and water.The organic layer is dried over sodium sulfate, filtered andconcentrated under reduced pressure so as to afford a foam. Flashchromatography on silica gel and elution with a graded mixture of hexaneand ethyl acetate will afford methyl6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside as a foam.

EXAMPLE 65 Preparation of

METHYL6-O-(2,3,6-TRI-O-BENZYL-4-DEOXY-4-HYDROXYMETHYL-α-GLUCOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

Methyl6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetytoxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.469 g, 2.593 mmol) is dissolved in hot toluene(20 ml) and methanol (80 ml) is added, followed by a few drops of 1 Mmethanolic sodium methoxide. The mixture is stirred at room temperatureduring 2 h. The reaction mixture is made neutral with Amberlite IR 120(H+) resin, filtered and concentrated under reduced pressure so as toafford methyl6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside as an amorphous solid.

EXAMPLE 66 Preparation of

METHYL6-O-(2,3,6-TRI-O-BENZYL-4-DEOXY-4-TRIFLUOROMETHYL-SULFONYLOXYMETHYL-.alpha.-D-GLUCOPYRANOSYL)-2,3,4-TRI-O-BENZYL-α-D-GLUCOPYRANOSIDE

To a solution of dry pyridine (0.46 ml) in dry methylene chloride (40ml) cooled to -15° C. is added trifluoromethane sulfonic anhydride (0.86ml). The mixture is stirred during 15 min at -10° C., then methyl6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.36 g, 2.593mmol) in methylene chloride (10 ml) is added. The mixture is stirredduring 1.5 h at -10° C. The reaction mixture is washed with water. Theorganic layer is dried over sodium sulfate, filtered and concentratedunder reduced pressure so as to afford an oil which will be the expectedtriflate methyl6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-trifluoromethylsulfonyloxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O -benzyl-α-D-glucopyranoside.

EXAMPLE 67 Preparation of

2,3,6-TRI-O-BENZYL-1,5-DIDEOXY-N-(2,3,6,TRI-O-BENZYL-4-DEOXY-1-(2,3,4-TRI-O-BENZYL-1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-4-α-D-GLUCOPYRANOSYL!METHYL)1,5-IMINO-D-GLUCITOL

A solution of methyl6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-trifluoromethylsulfonyloxymethyl-α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (1.8 g, 1.72 mmol) and2,3,6-tri-O-benzyl-1, 5-dideoxy-1,5-imino-D-glucitol (0.745 g, 1.72mmol) in ethanol-free chloroform (50 ml) is refluxed under nitrogenduring 48 h. The mixture is diluted in methylene chloride and washedsuccessively with a saturated aqueous solution of sodium bicarbonate andsaturated brine. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure so as to afford a foam.Flash chromatography on silica gel and elution with a graded mixture ofhexane and ethyl acetate will afford the expected amine2,3,6-tri-O-benzyl-1,5-dideoxy-N-(2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}1,5-imino-D-glucitol as an amorphous solid.

EXAMPLE 68 Preparation of

1,5-DIDEOXY-N-{4-DEOXY-1-(1-O-METHYL-6-O-α-D-GLUCOPYRANOSYL)-4-.alpha.-D-GLUCOPYRANOSYL!METHYL}1,5-IMINO-D-GLUCITOL

2,3,6-tri-O-benzyl-1,5-dideoxy-N-(2,3,6-tri-O-benzyl-4-deoxy-1-(2,3,4-tri-O-benzyl-1-O-methyl-6-O-α-D-glucopyranosol)-4-α-D-glucopyranosyl!methyl}1,5-imino-D-glucitol(1.3 g, 1.247 mmol) is dissolved in methanol (30 ml). Palladiumhydroxide 20% on charcoal (0.6 g) is added. The mixture is hydrogenatedduring 4 days at 3 atmospheres. The catalyst is removed by filtrationand the solvents are evaporated under reduced pressure. Flashchromatography on silica gel and elution with a graded mixture ofchloroform, methanol and water will afford the expected amine1,5-dideoxy-N-( 4-deoxy-1-(1-O-methyl-6-O-α-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}1,5-imino-D-glucitol as anamorphous solid.

EXAMPLE 69 Preparation of

1,5-DIDEOXY-1,5-(6-DEOXY-6-D-GLUCOPYRANOSYL)IMINO-D-GLUCITOL

1,5-dideoxy-1,5-(6-deoxy-1-O-methyl-6-α-D-glucopyranosyl)imino-D-glucitol(0.150 g, 0.442 mmol) is dissolved in a 1:1 mixture of water andtrifluoroacetic acid (10 ml). The mixture is stirred during 24 h at 0°C. The solvents are evaporated under reduced pressure so as to afford afoam. Chromatography on Amberlyst A26 OH⁻⁻ form will afford the expectedamine 1,5-dideoxy-1,5-(6-deoxy-6-D-glucopyranosyl)imino-D-glucitol.

EXAMPLE 70 Preparation of

5-AZIDO-3,6-DI-O-BENZYL-5-DEOXY-D-GLUCOFURANOSE

The azide5-azido-3,6-di-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranoside(U. G. Nayak and R. L. Whisler, J. Org. Chem., 33, 3582 (1968) (15.02 g,35.3 mmol) was dissolved at 0° C. in 100 ml of a 9:1 mixture oftrifluoroacetic acid and water. The mixture was stirred at 0° C. during2 h. The trifluoroacetic acid was evaporated under reduced pressure atroom temperature. The residue was taken with ether and washed withwater. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Flash chromatography on silica geland elution with a 1:1 mixture of hexane and ethyl acetate, followed byrecrystallization in a mixture of hexane and ethyl acetate afforded theexpected compound 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranose.

EXAMPLE 71 Preparation of

METHYL 5-AZIDO-3,6-DI-O-BENZYL-5-DEOXY-D-GLUCOFURANOSIDE

To a solution of 5-azido-3,6-di-O-benzyl-5-D-glucofuranose (10.23 g,26.5 mmol) in methylene chloride (170 ml) was added methanol (11 ml) andborontrifluoroetherate (1.5 ml). The mixture was stirred 24 h at roomtemperature. The reaction mixture was successively washed with asaturated aqueous solution of sodium bicarbonate and then with brine.The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Flash chromatography on silica geland elution with a 1:1 mixture of hexane and ethyl acetate affordedmethyl 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranoside as colorlessoil (9.15 g, 85%).

EXAMPLE 72 Preparation of

METHYL 5-AZIDO-2,3,6-TRI-O-BENZYL-5-DEOXY-D-GLUCOFURANOSIDE

To a suspension of sodium hydride (1.2 g, 27.5 mmol), 55% in mineraloil, washed three times with pentane) in anhydrous tetrahydrofuran (200ml) was added quickly dropwise the alcohol methyl5-azido-3,6-di-O-benzyl-5-deoxy-D-gluco-furanoside (9.15 g, 22.9 mmol)in tetrahydrofuran (50 ml) at room temperature and under nitrogen. Themixture was stirred during 3 h at room temperature. the mixture wasyellow. Then n-Bu₄ N⁺ I⁻⁻ (76 mg, 0.20 mmol) was added followed bybenzyl bromide (3.30 ml, 27.5 mmol) added dropwise. The mixture wasstirred overnight at room temperature. After hydrolysis with saturatedaqueous ammonium chloride tetrahydrofuran was evaporated under reducedpressure. The residue was diluted with water and extracted three timeswith ether. The organic phase was dried over sodium sulfate. Filtrationand evaporation under reduced pressure afforded an oil. Flashchromatography on silica gel and elution with a 20:80 mixture of ethylacetate and hexane afforded the expected compound methyl 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranoside as a colorless oil (10.88 g,97%).

EXAMPLE 73 Preparation of

5-AZIDO-2,3,6-TRI-O-BENZYL-5-DEOXY-D-GLUCOFURANOSE

Methyl 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofurano-side (10.8 g,22.2 mmol) was dissolved at room temperature in tetrahydrofuran (20 ml).The solution was cooled at -10° C. and trifluoroacetic acid (120 ml) wasadded dropwise followed by addition of water (20 ml). The mixture wasstirred at 0° C. during 24 h. The mixture was evaporated under reducedpressure without heating. The residue was taken with ether and washedwith water. The organic layer was dried over sodium sulfate, filteredand concentrated under reduced pressure. Flash chromatography on silicagel and elution with a 20:80 mixture of ethyl acetate and hexaneafforded 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranose as acolorless oil (9.63 g, 90%).

EXAMPLE 74 Preparation of

5-AZIDO-2,3,6-TRI-O-BENZYL-5-DEOXY-D-GLUCONIC ACID-γ-LACTONE

To a solution of the lactol5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranose (9.36 g, 20 mmol) inacetone (240 ml) cooled to 0° C., Jones' reagent 2 M (11.5 ml) was addeddropwise until the color was orange. The excess of Jones' reagent wasdestroyed with 2-propanol (0.5 ml). The mixture was concentrated underreduced pressure. The residue was taken with water and extracted withether. The organic phase was dried with sodium sulfate, filtered andconcentrated under reduced pressure so as to afford an oil. Flashchromatography on silica gel and elution with a 1:9 mixture of ethylacetate and hexane afforded the γ-lactone5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-gluconic acid-γ-lactone.

EXAMPLE 75 Preparation of

2,3,6-TRI-O-BENZYL-5-DEOXY-D-GLUCONIC ACID-δ-LACTAM

To a solution of the lactone5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-gluconic acid-γ-lactone (8.16 g, 17mmol) in ethanol (180 ml) was added lindlar catalyst (1.7 g). Themixture was hydrogenated under atmospheric pressure during 24 h.Filtration and evaporation under reduced pressure afforded an oil whichwas crystallized in a mixture of hexane and ether. The lactam2,3,6-tri-O-benzyl-5-deoxy-D-gluconic acid-δ-lactam was obtained aswhite crystals (7.4 g, 96%). mp: 85°-85.5° C.

By substituting those specifically mentioned final products set forthabove which are analogous to 1,5-dideoxy-1,5- (6-deoxy-1-O-methyl-6-α-D-glucopyranosyl)imino!-D-glucitol and by following the teachings ofExamples 2 through 6, there will be produced the final compounds of thisinvention (Formula I) which are analogous to the final compound ofExample 6. Similarly, by preparing the appropriately positioned bromoderivative (analogous to methyl-6-bromo-6-deoxy-α-D-glucopyranoside ofExample 1) of the above mentioned glycosyl moieties utilized for thecondensations reactions with 1-deoxy nojirimycin, and by following theteachings of Example 1, there will be produced the final productsanalogous to the product of Example 1. these compounds are set forth asfollows:

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-6,7-dideoxy-7-D-glucoheptopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(1-deoxy-D-fructofuranosyl)imino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(4-deoxy-4-D-glucopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-6-deoxy-1-(6-O-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-6,7-dideoxy-l-(6-O-D-glucopyranosyl)-7-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(4-deoxy-4-D-glucopyranosyl)methylimino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-4-deoxy-1-(4-O-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-{2(1-D-arabinofuranose)ethyl!imino}-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-4-deoxy-1-(6-O-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-{4-deoxy-1-(4-O-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-{4-deoxy-1-(6-O-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(6-deoxy-1-O-methyl-6-β-D-glucopyranosyl)-imino-D -glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(6,7-dideoxy-1-O-methyl-7-.beta.-D-glucoheptopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(1-deoxy-2-O-methyl-β-D-fructofuranosyl)imino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(4-deoxy-1-O-methyl-4-β-D-glucopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-6-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-6,7-dideoxy-1-(1-O-methyl-6-O-β-D-glucopyranosyl)-7-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-(4-deoxy-1-O-methyl-4-β-D-glucopyranosyl)methylimino!-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-4-deoxy-1-(1-O-methyl-4-O-8-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-1,5-{2-(1-O-methyl-1-β-D-arabinofuranosyl)ethyl!imino}-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-{4-deoxy-1-(1-O-methyl-4-O-.beta.-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-4-O(α,D-glucopyranosyl)-N-{4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-6,7-dideoxy-7-D-glucoheptopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(1-deoxy-D-fructofuranosyl)imino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(4-deoxy-4-D-glucopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-6-deoxy-1-(6-O-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-6,7-dideoxy-1-(6-O-D-glucopyranosyl)-7-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(4-deoxy-4-D-glucopyranosyl)methylimino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-4-deoxy-1-(4-O-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-{2(1-D-arabinofuranose)ethyl!imino}-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-4-deoxy-1-(6-O-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-{4-deoxy-1-(4-O-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-{4-deoxy-1-(6-O-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(6-deoxy-1-O-methyl-6-β-D-glucopyranosyl) -imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(6,7-dideoxy-1-O-methyl-7-.beta.-D-glucoheptopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(1-deoxy-2-O-methyl-β-D-fructofuranosyl)imino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(4-deoxy-1-O-methyl-4-β-D-glucopyranosyl)imino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-6-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-6,7-dideoxy-1-(1-O-methyl-6-O-β-D-glucopyranosyl)-7-α-D-glucoheptopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-(4-deoxy-1-O-methyl-4-β-D-glucopyranosyl)methylimino!-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-4-deoxy-1-(1-O-methyl-4-O-.beta.-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-1,5-{2-(1-O-methyl-1-B-D-arabinofuranosyl)ethyl!imino}-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-α-D-glucopyranosyl!-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-(4-deoxy-1-(1-O-methyl-4-O-.beta.-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol,

1,5-Dideoxy-6-O(α,D-glucopyranosyl)-N-(4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-4-α-D-glucopyranosyl!methyl}-1,5-imino-D-glucitol.

Enzymes which catalyze the hydrolysis of complex carbohydrates, e.g.α-glycosidases, convert nonabsorbable carbohydrates into absorbablesugars. The rapid action of these enzymes, particularly following theintake of high levels of carbohydrates, lead to acute high levels inblood glucose which, in the case diabetics, lead to undesirablemanifestations, thus it has been a long-sought goal to find compoundswhich will obviate the hyperglycemia caused by dietary improprieties.Similarly, in the case of obesity the control of high levels of bloodglucose, with its subsequent conversion to fat, caused by the catalysisof carbohydrates has inspired the quest for compounds which will obviatethe problems associated with dietary improprieties.

The compounds of this invention (I) are potent and long-lastinginhibitors of α-glucosidase and, by standard laboratory methods fordetermining serum glucose levels, are shown to be useful for thetreatment of disease states caused by the under utilization and/oroverproduction of serum glucose without adversely affecting the rate oftransport across cell membranes. Thus, the compounds are useful in thetreatment of diabetes and obesity.

In the practice of this invention, an effective amount of a compound ofthis invention is that amount required to reduce the amount of serumglucose (relative to a control) following the ingestion of carbohydratesconvertible to absorbable glucose. The specific dosage for the treatmentof any specific patient suffering from either disease state will dependupon such factors as size, type and age of the patient as well as theseverity of the disease state, all of which are factors normallyfamiliar to and considered by the attending diagnostician treating thepatient. Generally, the compounds are to be administered orally at adose of 0.2 to 20 milligrams per kilogram of body weight (MPK) with adose of 0.5 to 5 MPK being preferred. The compounds preferable are to beadministered orally at mealtimes in single or multiple unit dosescontaining 25 mg to 250 mg. Of course, in the treatment of obesity, theterm includes the practice of the disease as well as continuedadministration of dose regimens suitable for the maintenance of thedesired weight for the patient.

It is also to be found that the compounds of the instant invention (I)will exert an inhibitory effect on glycosidase enzymes that areessential for elaboration of the final structure of the oligosaccharideside-chains of glycoproteins, particularly the HIV (gp 120)glycoprotein. Suitable assay techniques, e.g. syncytial formation, thereverse transcriptase assay, immunofluorescence tests and electionmicroscopy, may be used to evaluate the effects on HIV vital growth andfor determining dose regimens. Antivital effects may be confirmed byimmunofluorescence with serum for virally infected patients. In thetreatment of the HIV related disease states, as well as other retroviralglycoprotein-related disease states, unlike the treatment of diabetesand obesity, the compounds of this invention may be administered byparenteral means; specific doses being within the above stated doserange for treatment of diabetes and obesity.

In practicing the end-use application of the compounds of thisinvention, the compounds are preferably incorporated in a pharmaceuticalformulation comprising a pharmaceutical carrier in admixture with acompound of this invention. The term "pharmaceutical carrier" refers toknown pharmaceutical excipients useful in formulating pharmaceuticallyactive compounds for internal administration to animals, and which aresubstantially nontoxic and nonsensitizing under conditions of use. Thecompositions can be prepared by known techniques for the preparation oftablets, capsules, elixirs, syrups, emulsions, dispersions and wettableand effervescent powders, and can contain suitable excipients known tobe useful in the preparation of the particular type of compositiondesired. Suitable pharmaceutical carriers and formulation techniques arefound in standard texts, such as Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa.

We claim:
 1. A compound of the formula ##STR7## and the pharmaceuticallyacceptable acid addition salts thereof wherein n is zero, 1 or 2,R is aglycosyl moiety containing 1 to 3 hexose or penrose units, said unitsbearing a methoxy moiety at the anomeric carbon atom of the terminalhexose or pentose unit, and one of R₁ or R₂ is H and the other isα-D-glucopyranosyl.
 2. A compound of claim 1 wherein R₁ isα-D-glucopyranosyl and R₂ is H.
 3. A compound of claim 1 wherein R₂ isα-D-glucopyranosyl and R₁ is H.
 4. A compound of claim 1 wherein n isone.
 5. A compound of claim 1, said compound being 1,5-dideoxy-4-O-(α,D-glucopyranosyl)-1,5- (6-deoxy-1-O-methyl-6-α,D-glucopyranosyl)imino!-D-glucitol.
 6. A pharmaceuticalcomposition comprising the compound according to any one of claims 1through 5 and an acceptable pharmaceutical carrier.
 7. A process fortreating hyperglycemia which comprises administering to a patientsuffering from hyperglycemia a therapeutically effective amount of acompound of claim
 1. 8. A process for treating obesity which comprisesadministering to a patient suffering from obesity a therapeuticallyeffective amount of a compound of claim
 1. 9. A process for preparing acompound of the formula ##STR8## or the pharmaceutically acceptable acidaddition salts thereof wherein n is zero, 1 or 2,R is a glycosyl moietycontaining 1 to 3 hexose or pentose units, said units optionally bearinga methoxy moiety at the anomeric carbon atom of the terminal hexose orpentose unit, and one of R₁ and R₂ is H and the other isα-D-glucopyranosyl, which comprises the reactions (a) condensing acompound of the formula ##STR9## wherein n is zero, one or two, R' is aglycosyl moiety as defined for R in Formula II wherein its OH radicalsbear a hydroxy-protecting group, Pg is a hydroxy-protecting group, andone of R₃ and R₄ is a hydroxy-protecting group and the other is H, witha compound of the formula ##STR10## to produce a compound of theformulae ##STR11## followed by the removal of any hydroxy-protectinggroups and, if necessary, neutralizing any ammonium salts, and (b)condensing a compound of the formula ##STR12## wherein one of R₁ and R₂is H and the other is an α-D-glucopyranosyl moiety with a compound ofthe formula X-(CH₂)_(n) R wherein X is bromo, n is zero, one or two, andR is as defined for Formula II, said reactions (a) and (b) producingcompounds of the formula ##STR13## wherein R, R₁, R₂ and n are asdefined in Formula II, and optionally converting said compounds to theirpharmaceutically acceptable salts.